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- PDB-7kk6: Structure of the catalytic domain of PARP1 in complex with veliparib -

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Basic information

Entry
Database: PDB / ID: 7kk6
TitleStructure of the catalytic domain of PARP1 in complex with veliparib
ComponentsPoly [ADP-ribose] polymerase 1
KeywordsTRANSFERASE / PARP1
Function / homology
Function and homology information


NAD+-histone H2BS6 serine ADP-ribosyltransferase activity / NAD+-histone H3S10 serine ADP-ribosyltransferase activity / NAD+-histone H2BE35 glutamate ADP-ribosyltransferase activity / regulation of base-excision repair / positive regulation of myofibroblast differentiation / negative regulation of ATP biosynthetic process / NAD+-protein-tyrosine ADP-ribosyltransferase activity / NAD+-protein-histidine ADP-ribosyltransferase activity / carbohydrate biosynthetic process / regulation of circadian sleep/wake cycle, non-REM sleep ...NAD+-histone H2BS6 serine ADP-ribosyltransferase activity / NAD+-histone H3S10 serine ADP-ribosyltransferase activity / NAD+-histone H2BE35 glutamate ADP-ribosyltransferase activity / regulation of base-excision repair / positive regulation of myofibroblast differentiation / negative regulation of ATP biosynthetic process / NAD+-protein-tyrosine ADP-ribosyltransferase activity / NAD+-protein-histidine ADP-ribosyltransferase activity / carbohydrate biosynthetic process / regulation of circadian sleep/wake cycle, non-REM sleep / positive regulation of single strand break repair / vRNA Synthesis / negative regulation of adipose tissue development / NAD+-protein-serine ADP-ribosyltransferase activity / NAD DNA ADP-ribosyltransferase activity / NAD+- protein-aspartate ADP-ribosyltransferase activity / NAD+-protein-glutamate ADP-ribosyltransferase activity / DNA ADP-ribosylation / mitochondrial DNA metabolic process / regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / signal transduction involved in regulation of gene expression / replication fork reversal / positive regulation of necroptotic process / regulation of catalytic activity / ATP generation from poly-ADP-D-ribose / transcription regulator activator activity / HDR through MMEJ (alt-NHEJ) / : / positive regulation of DNA-templated transcription, elongation / NAD+ ADP-ribosyltransferase / cellular response to zinc ion / negative regulation of telomere maintenance via telomere lengthening / positive regulation of intracellular estrogen receptor signaling pathway / protein auto-ADP-ribosylation / positive regulation of mitochondrial depolarization / response to aldosterone / mitochondrial DNA repair / negative regulation of cGAS/STING signaling pathway / protein poly-ADP-ribosylation / positive regulation of double-strand break repair via homologous recombination / positive regulation of cardiac muscle hypertrophy / negative regulation of transcription elongation by RNA polymerase II / nuclear replication fork / site of DNA damage / NAD+-protein ADP-ribosyltransferase activity / R-SMAD binding / positive regulation of SMAD protein signal transduction / macrophage differentiation / protein autoprocessing / decidualization / NAD+ ADP-ribosyltransferase activity / Transferases; Glycosyltransferases; Pentosyltransferases / POLB-Dependent Long Patch Base Excision Repair / nucleosome binding / SUMOylation of DNA damage response and repair proteins / protein localization to chromatin / telomere maintenance / negative regulation of innate immune response / nucleotidyltransferase activity / mitochondrion organization / transforming growth factor beta receptor signaling pathway / cellular response to nerve growth factor stimulus / protein-DNA complex / nuclear estrogen receptor binding / response to gamma radiation / Downregulation of SMAD2/3:SMAD4 transcriptional activity / DNA Damage Recognition in GG-NER / protein modification process / Dual Incision in GG-NER / Formation of Incision Complex in GG-NER / positive regulation of protein localization to nucleus / cellular response to insulin stimulus / histone deacetylase binding / cellular response to amyloid-beta / NAD binding / cellular response to UV / regulation of protein localization / double-strand break repair / nuclear envelope / cellular response to oxidative stress / site of double-strand break / positive regulation of canonical NF-kappaB signal transduction / transcription regulator complex / RNA polymerase II-specific DNA-binding transcription factor binding / transcription by RNA polymerase II / chromosome, telomeric region / damaged DNA binding / nuclear body / innate immune response / DNA repair / negative regulation of DNA-templated transcription / apoptotic process / ubiquitin protein ligase binding / DNA damage response / chromatin binding / chromatin / nucleolus / protein kinase binding / negative regulation of transcription by RNA polymerase II / enzyme binding
Similarity search - Function
: / PADR1, N-terminal helical domain / PADR1 domain profile. / Poly [ADP-ribose] polymerase / PADR1 domain / PADR1 domain superfamily / PADR1 domain, zinc ribbon fold / PADR1 / Zinc finger poly(ADP-ribose) polymerase (PARP)-type signature. / Zinc finger, PARP-type superfamily ...: / PADR1, N-terminal helical domain / PADR1 domain profile. / Poly [ADP-ribose] polymerase / PADR1 domain / PADR1 domain superfamily / PADR1 domain, zinc ribbon fold / PADR1 / Zinc finger poly(ADP-ribose) polymerase (PARP)-type signature. / Zinc finger, PARP-type superfamily / Poly(ADP-ribose) polymerase and DNA-Ligase Zn-finger region / Zinc finger poly(ADP-ribose) polymerase (PARP)-type profile. / Poly(ADP-ribose) polymerase and DNA-Ligase Zn-finger region / Zinc finger, PARP-type / WGR domain profile. / Poly(ADP-ribose) polymerase, regulatory domain / WGR domain / WGR domain superfamily / WGR domain / Proposed nucleic acid binding domain / Poly(ADP-ribose) polymerase, regulatory domain superfamily / Poly(ADP-ribose) polymerase, regulatory domain / PARP alpha-helical domain profile. / BRCA1 C Terminus (BRCT) domain / Poly(ADP-ribose) polymerase catalytic domain / Poly(ADP-ribose) polymerase, catalytic domain / PARP catalytic domain profile. / breast cancer carboxy-terminal domain / BRCT domain profile. / BRCT domain / BRCT domain superfamily
Similarity search - Domain/homology
Chem-78P / Poly [ADP-ribose] polymerase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.06 Å
AuthorsGajiwala, K.S. / Ryan, K.
CitationJournal: J.Biol.Chem. / Year: 2021
Title: Dissecting the molecular determinants of clinical PARP1 inhibitor selectivity for tankyrase1.
Authors: Ryan, K. / Bolanos, B. / Smith, M. / Palde, P.B. / Cuenca, P.D. / VanArsdale, T.L. / Niessen, S. / Zhang, L. / Behenna, D. / Ornelas, M.A. / Tran, K.T. / Kaiser, S. / Lum, L. / Stewart, A. / Gajiwala, K.S.
History
DepositionOct 27, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 6, 2021Provider: repository / Type: Initial release
Revision 1.1Jan 13, 2021Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed ..._citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Apr 28, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.3Oct 18, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
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Assembly

Deposited unit
A: Poly [ADP-ribose] polymerase 1
B: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)79,6519
Polymers78,6822
Non-polymers9697
Water3,099172
1
A: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,8735
Polymers39,3411
Non-polymers5324
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,7774
Polymers39,3411
Non-polymers4363
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)48.540, 91.410, 162.750
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Poly [ADP-ribose] polymerase 1 / PARP-1 / ADP-ribosyltransferase diphtheria toxin-like 1 / ARTD1 / DNA ADP-ribosyltransferase PARP1 ...PARP-1 / ADP-ribosyltransferase diphtheria toxin-like 1 / ARTD1 / DNA ADP-ribosyltransferase PARP1 / NAD(+) ADP-ribosyltransferase 1 / ADPRT 1 / Poly[ADP-ribose] synthase 1 / Protein poly-ADP-ribosyltransferase PARP1


Mass: 39340.988 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PARP1, ADPRT, PPOL / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P09874, NAD+ ADP-ribosyltransferase, Transferases; Glycosyltransferases; Pentosyltransferases
#2: Chemical ChemComp-78P / (2R)-2-(7-carbamoyl-1H-benzimidazol-2-yl)-2-methylpyrrolidinium / Veliparib / Veliparib


Mass: 244.292 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C13H16N4O / Feature type: SUBJECT OF INVESTIGATION / Comment: anticancer, inhibitor*YM
#3: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 172 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.29 Å3/Da / Density % sol: 46.39 %
Crystal growTemperature: 277 K / Method: vapor diffusion
Details: Buffer: 0.1 M HEPES (pH 7.00) Precipitant: 3.0 M Ammonium sulfate

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Data collection

DiffractionMean temperature: 98 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Aug 7, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.06→60.78 Å / Num. obs: 29062 / % possible obs: 91.3 % / Redundancy: 6.2 % / CC1/2: 0.981 / Net I/σ(I): 6.4
Reflection shellResolution: 2.06→2.311 Å / Num. unique obs: 1453 / CC1/2: 0.388

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
PDB_EXTRACT3.25data extraction
Aimlessdata scaling
PHASERphasing
autoPROCdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5ws1

5ws1


Resolution: 2.06→46.65 Å / Cor.coef. Fo:Fc: 0.936 / Cor.coef. Fo:Fc free: 0.888 / SU R Cruickshank DPI: 0.478 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.507 / SU Rfree Blow DPI: 0.288 / SU Rfree Cruickshank DPI: 0.288
RfactorNum. reflection% reflectionSelection details
Rfree0.271 1383 4.76 %RANDOM
Rwork0.206 ---
obs0.209 29062 63.1 %-
Displacement parametersBiso max: 115.64 Å2 / Biso mean: 42.47 Å2 / Biso min: 10.28 Å2
Baniso -1Baniso -2Baniso -3
1-0.3883 Å20 Å20 Å2
2---0.1269 Å20 Å2
3----0.2614 Å2
Refine analyzeLuzzati coordinate error obs: 0.33 Å
Refinement stepCycle: final / Resolution: 2.06→46.65 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5501 0 61 172 5734
Biso mean--43.88 37.5 -
Num. residues----700
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2024SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes942HARMONIC5
X-RAY DIFFRACTIONt_it5665HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion733SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact6331SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d5665HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg7654HARMONIC21.22
X-RAY DIFFRACTIONt_omega_torsion3.16
X-RAY DIFFRACTIONt_other_torsion21.4
LS refinement shellResolution: 2.06→2.23 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2907 33 5.67 %
Rwork0.2089 549 -
all0.2142 582 -
obs--5.9 %

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